This new component of the Center seeks to elucidate the role that a large set of genes comprehensively representing neurobiological systems involved in drug-related processes plays in the risk for substance use disorders (SUD). The genetic investigation of the major neurobiological systems that have been shown to work in concert in drug-related behavior and in drug response will take advantage of hypothesis-driven research while having a wide scope commensurate with the complexity of etiologic mechanisms. The systemic approach can considerably increase the prior probability of detecting true genetic associations, place these findings in the context of current and expanding neurobiological knowledge, and relate them to the extensive developmental psychological, psychopathological, biological, and environmental information available on the large sample of CEDAR subjects. CEDAR's high-risk/family design and uniquely rich longitudinal data and large sample enable application of the state-of-the-art genetic methods to qualitative (diagnostic) and quantitative definitions of the SUD liability phenotype, as well as to potential biobehavioral mediators and environmental moderators of its development. Both family-based and stratification-corrected population-based {genomic control) analytic approaches will be used, taking into account sex and ethnic variation. Functional neurochemical and fMRI studies will examine the biological substrate of the genetic associations found. As the majority of CEDAR's children will pass through the modal age of SUD risk in the ensuing five-year period, the genetic contribution to the transition from substance use to SUD as well as to the intergenerational transmission of the risk will be explored.